EA032117B1 - Use of the anti-alpha-v integrin antibody di17e6 in the production of a medicament and treatment of prostate cancer, method of treating castration-resistant prostate cancer (crpc), method of declining the psa level, method of reducing pain occurring in prostate cancer - Google Patents

Abstract

The invention relates to the use of the anti-αv integrin antibody DI17E6 or a biologically active variant or modification thereof, wherein said variant or modification comprises a constant region which is at least 80-98% identical in amino acid sequence compared to the constant region of DI17E6, for the treatment or production of a medicament for treating patients suffering from castration-resistant prostate cancer and to a corresponding method of the treatment.

Description

The invention relates to the use of an antibody ΌΙ17Ε6 to integrin αν or a biologically active variant or modification thereof, wherein said variant or modification contains a constant region that is at least 80-98% identical in amino acid sequence to the constant region ΌΙ17Ε6 for the treatment or manufacture of a medicament for treatment of patients suffering from castration-resistant prostate cancer, and to an appropriate method of treatment.

032117 Β1

032117 Β1

FIELD OF THE INVENTION

The invention is directed to the treatment of prostate cancer with antibodies. The invention primarily relates to the administration of antibodies to integrin alpha-ν (receptor) to patients suffering from prostate cancer, in particular to castration-resistant prostate cancer (saphenophenoglobin pseudomonas pylori, SCRS) without chemotherapy or after chemotherapy, optionally accompanied by metastases in the lymph nodes and bone tissue (tSCRS). Specifically, the invention relates to the treatment of these patients with anti-angiogenic antibodies 7-7 and their structural mutants.

State of the art

Prostate cancer is most widespread in the United States after skin cancer and is the second most common cause of death in male cancer patients.

Prostate cancer is divided into 4 stages. At stage I, prostate cancer only occurs in the prostate and cannot be detected by external rectal examination or visualized by scanning. In stage II of prostate cancer, the tumor can grow inside the prostate without spreading beyond it, while in stage III the cancer spreads beyond the prostate, but to a minimum. Often, stage III prostate cancer only spreads to nearby tissues, such as seminal vesicles. Finally, in stage IV, the cancer spreads outside the prostate to other tissues, such as the lymph nodes, bones, liver and / or lungs or brain.

The spectrum of types of prostate cancer progressing regardless of testosterone levels after castration includes tumors that have varying degrees and duration of response to primary hormone treatment and clinical manifestations that range from: only an increase in the level of prostate-specific antigen (PSA), an increase in PSA with spread to bone and / or soft tissues or mainly a set of internal diseases.

Current treatments for prostate cancer include surgical castration, chemical castration, or a combination of surgical and chemical castration. Removal of the testes, the main organ producing testosterone, reduces the level of circulating androgens to less than 5% of the normal level. A decrease in androgen levels inhibits the growth of a prostate tumor. Although surgical castration has a direct antitumor effect, its antitumor effect may be temporary. Surgical castration often leads to clone selection of androgen-independent prostate tumor cells. The consequence of this is the re-growth of a prostate tumor in a form that proliferates without stimulation with testosterone or dihydrotestosterone. Chemical castration (also called medical castration) is often used instead of surgical castration as an initial stage of treatment. Despite its significant advantage, recommendations for its use in treating men with prostate cancer remain relatively limited and usually depend on the stage of the disease.

Treatment options include surgical methods, such as radical prostatectomy, in which the prostate is completely removed, and irradiation carried out either by an external beam, which provides the prostate with a dose of radiation from the outside of the body, or by low-dose radioactive inclusions implanted into the prostate and locally killing cancer cells. Anti-androgen hormone therapy, either alone or in combination with surgery or radiation, is also used in the treatment of prostate cancer. The goal of hormone therapy is usually to block the production of hormones in the pituitary gland, which stimulates the production of testosterone, by castration or administration of hormone analogues and requires the injection of these hormone analogues into patients for a long time. Finally, chemotherapeutic approaches are used to treat advanced prostate cancer, usually as a last resort when all other approaches have been exhausted. In recent years, a combination of docetaxel and prednisone has been developed as a new standard in the treatment (use) of patients in whom cancer has progressed with the suppression of androgens.

None of the treatments described above is salvage, and prostate cancer, being initially androgen-dependent, often progresses despite surgical treatment or hormone-based treatment, and after a while becomes resistant, eventually leading to a type of cancer called cancer of hormonal resistance or cancer resistant to castration (Sayntyop geGoyt Sapseg, SCRS).

The clinical manifestations of the disease in SCRS are usually associated with bone metastases and may include pain, pathological injuries and compression of the spinal cord, with local relapses that may be associated with malaise in the spine, impaired renal function due to compression of the ureters, obstruction of the outlet of the bladder and sexual dysfunction. In addition, although bone cancer is the predominant consequence of SCRS, patients may develop metastases in the soft tissues (in the lymph nodes) and visceral metastases in the liver, lungs, brain, and other organs. Patients with SCRS respond minimally to chemotherapy, and most patients die due to progressive prostate cancer within 20 months of starting treatment. Typically, in patients with castration-resistant prostate cancer with bone metastases, bisphosphonates are used.

- 1 032117

It was found that prostate tumors remain dormant and are not clinically detected until they begin to secrete angiogenic factors and regulate the expression of angiogenesis inhibitors with suppression. As a rule, it can be argued that angiogenesis is extremely important for the genesis of prostate tumors. Therefore, it was not completely unexpected that antiangiogenic agents inhibit the growth of prostate cancer cells.

In prostate cancer, tumor cells express an abnormal set of integrins and are surrounded by a noticeably widespread extracellular matrix (ECM). These changes have profound consequences, with each integrin regulating specific cellular functions. Expression of β3 and β1 subunits activates specific signaling pathways and supports the functions of various cancer cells. Cancer cells have a unique need for β3 to increase sbc2 levels and sbc2 kinase activity. These effects are specific for β3 and are not observed in β6. Regulation with stimulation of integrin variants β3 and β6 has been described. Ζ1ιοη§ c1 a1. (Sapseg Kekeatsi 1999; 59, 1655-1664) used human prostate cancer cells isolated from 16 surgical specimens to show that these cells express ανβ3, in contrast to normal prostate epithelial cells. In a similar way, it was found that ανβ6 is expressed in an adenocarcinoma (L e1 a1; Mo1eci1ag apb Ce11u1ag Vu1odu 2007; 27, 4444).

Apparently, the use of integrin inhibitors affects both the survival of cancer cells and angiogenesis, since integrins are expressed by both tumor cells and endothelial cells. Although the effects on tumor growth and angiogenesis are difficult to separate, the maximum effect of these inhibitors can be predicted when the integrin target is expressed by the cells of both the tumor and the endothelium.

Bones are the most common place for metastases in prostate cancer. BEAP e1 a1. (Mo1ci1ag Tietaru 2005; 12, 634-643) showed the positive effect of alpha-v integrins on the survival of prostate tumor cells in the bones. Analysis of bone implants in human prostate cancer showed that intratumoral administration of small interfering RNAs (δίΡΝΑδ) integrin alpha-ν encapsulated in liposomes significantly inhibits the growth of PC3 tumors in the bones and enhances apoptosis of prostate tumor cells. Further studies (McCabe e1 a1., Optodepe 2007; 26, 6238-6243) showed that activation of integrin ανβ3 in tumor cells is necessary for recognition of key bone-specific matrix proteins. These data suggest that ανβ3 integrin modulates the growth of prostate cancer cells with distant metastasis.

Since integrins mediate interactions between tumor cells and the bone microenvironment and enhance bone growth, the potential use of integrin inhibitors is to prevent bone damage in prostate cancer. These lesions are osteoplastic and / or osteolytic and are often found in patients with prostate cancer (over 80% of patients with prostate cancer according to autopsy have bone metastases).

Recent studies have shown that ανβ3 integrin promotes bone growth mediated by prostate cancer cells that metastasize to the bone, and also point to ανβ3 as a potential therapeutic target for blocking osteoblastic lesions in prostate cancer. Immunohistochemical analysis demonstrated the presence of integrin αν in a large proportion of tissue samples of human prostate cancer.

These and other results suggest that anti-integrin agents may have both direct and indirect antitumor activity. However, there is only a few clinical evidence that peptide or non-peptide integrin inhibitors are effective in the treatment of prostate cancer.

Thus, there is a need to provide an active anti-integrin agent for use in the treatment of prostate cancer, especially resistant to castration of prostate cancer with the development of bone metastases.

SUMMARY OF THE INVENTION

Applicants have found that the known monoclonal antibodies ΌΙ-17Ε6 to integrin alpha-ν (designated here as EMK.62242 or ΕΜΌ 525797) are highly effective in (ί) monotherapy-based clinical prescriptions and (and) in combinatorial clinical prescriptions in conjunction with hormonal agents, and / or chemotherapeutic agents, and / or tyrosine kinase inhibitors, or other angiogenesis inhibitors in the treatment of prostate cancer.

In a first aspect of the invention, in clinical trials, it was found that known specifically engineered monoclonal antibodies (TAb) ΌΙ17Ε6 to integrin alpha-ν are well tolerated by patients with prostate tumors without noticeable side effects at doses of TAbI of at least 500 mg administered every two weeks by infusion into during the treatment period of at least 4 weeks (Fig. 3, table. 3).

In a second aspect of the invention, it was found that the administration of ΌΙ17Ε6 in doses of at least 500 mg every two weeks is effective in the treatment of prostate cancer, preferably resistant to castration of prostate cancer (SCRS). As a result, the number of circulating tumor originating from the prostate

- 2 032117 cells (CTC) in the blood of these patients decreased significantly during the treatment period, even if this number was initially (at the beginning of treatment) very high (Fig. 1).

In a third aspect of the invention, it was found that the level of prostate-specific antigen (PSA) in patients with SCRS can be significantly reduced. The effect depends on the duration of treatment and the condition of the disease in the patient. As a rule, after 5 or more months of treatment, it is possible to achieve PSA levels that correspond in less progressive cases to PSA levels in healthy men, in more acute cases, when the PSA level was catastrophically high at the beginning of antibody treatment, its level after treatment could be reduced by more than 10 times (Fig. 4, 5).

In a fourth aspect of the invention, it can be demonstrated that by administering ΌΙ17Ε6 in a dose of at least 500 mg every two weeks, metastatic manifestations in the bones and lymph nodes can be significantly reduced.

In a further aspect of the invention, it can be shown that ΌΙ17Ε6 gives a dose-dependent response in patients with prostate cancer, preferably in patients with castration-resistant prostate cancer (SCRS), with increased efficacy at higher doses, with a dose of approximately 500 mg and higher every 2 weeks is effective, while administering a dose of ΌΙ17Ε6 of approximately 250 mg or lower is ineffective in prostate cancer, preferably in patients with SCRS (Figs. 3, 5).

It should be noted that ΌΙ17Ε6 is mainly effective in the monotherapy regimen where no additional cytotoxic drug was administered (such as kabacitaxel, docetaxel, doxorubicin, irinotecan, etc.). For the first time, engineered monoclonal antibodies have been found to be effective in tumor therapy without the need for a chemotherapeutic agent.

It should be further noted that according to the first results of these clinical trials, ΌΙ17Ε6 is apparently the more effective the more the disease progressed. So, ΌΙ17Ε6 has a stronger effect on the levels of PSA, circulating tumor cells and metastases in patients after ineffective hormone and / or chemotherapy and even after surgery, such as prostatectomy, compared with patients in a less progressive disease without such surgery or even without a preliminary course of treatment with chemotherapeutic agents and / or hormones. ΌΙ17Ε6 is a very promising treatment for SCRS, especially in patients with advanced disease or a disease in the last stage after treatment with chemotherapy.

An additional result is that ΌΙ17Ε6 is able to induce a decrease and destruction of the tumor (Fig. 6), especially with dense prostate tumors or tumor-derived metastases resistant to chemotherapy and / or radiotherapy.

Moreover, there is evidence that ΌΙ17Ε6 (with monotherapy) relieves the pain that usually accompanies prostate cancer. Thus, the drug is advantageous in recording pain and pain interference parameter (Figs. 4B, 5B). It can be observed that pain relief during treatment correlates with a decrease in PSA levels in these patients.

ΌΙ17Ε6 is well tolerated without premedication and does not show clinically significant dose-dependent changes in the established safety parameters, such as dangerous side effects associated with the use of the drug (1gca1tsc stsgdsu abuegke suspension ΤΕΑΕ) (Table 3).

In a further aspect of the invention, it can be shown that there is a strong correlation between the biomarkers of bone metabolism, including 8TC-1, ΑΌΑΜΤ8-1, M30, M65, GO6 and ΙΕ8, and dosage levels (Fig. 7). At high doses above 1500 mg, a significant decrease in osteopontin levels can be observed in most patients with SCRS.

The pharmacokinetic profile of ΌΙ17Ε6 depends on the dose after single and multiple dosing with a half-life of approximately 250 hours at a dose level of 1500 mg.

The results of phase 1 safety trials for unencrypted studies indicate that repeated infusions of the single agent ΌΙ17Ε6 (ΕΜΌ 525797) at each of the four dosage levels are well tolerated and are safe for patients with tSCRS and a progressive disease, preferably after prior chemotherapy. No dose-limiting toxicity was observed (Boke-Ntishd ΙοχίοίΙν. ET), and there were no reactions to the infusion. As for the dose, there were no trends in the distribution of TEAE, Νί.Ί-ί.'ΤΕΑΕ gradations (version 3.0), or the relationship with the drug. In addition, there is no evidence of the accumulation of any specific events within individual groups. Eleven patients had manifestations of TEAE that are considered to be related to the drug. In this regard, skin symptoms such as itching, redness of the skin and rash, which were observed in only 4 patients, are predictable side effects associated with ΌΙ17Ε6 (ΕΜΌ 525797), due to the fact that integrins are responsible for maintaining the phenotype of the epithelium. Symptoms of inflammation of the mucosa and swollen tongue may also be characteristic of the mechanism of action ΕΜΌ 525797, however, along with fatigue, they can also be signs of a concomitant disease. Shifts in hematological and biochemical toxicity observed in 8 patients can also be explained by the underlying disease, as well as the effect of concomitant drugs.

Evaluation of the pharmacokinetics (FC) profile after single and multiple doses of the study drug suggests that ΌΙ17Ε6 (ΕΜΌ 525797) behaves in accordance with the model

- 3,032,117 receptor-mediated receptors, as described for other antibodies targeting membrane-bound receptors. In accordance with the results of an early stage of the study in healthy volunteers, FC17176 (525797) in patients with tSCRS exhibits a dose dependence with excretion previously determined by the availability of unbound receptors. It can be assumed that at all doses used in this study, at doses of 1000 mg and above, almost all receptors are saturated and give a minimal contribution to drug elimination. In some patients (16%), immunological antibodies to ΌΙ17ΌΙ6 can be detected, but their contribution to FC or safety could not be established.

In patients with castration-resistant prostate cancer with bone metastases after previous chemotherapy, the expected average life time without disease progression is from 8 to 10 weeks. Evaluation of antitumor activity showed that ΌΙ17Ε6 (ΕΜΌ 525797) with single-agent therapy provided an objective partial tumor response in one patient in a group with a dose of 500 mg. In 9 out of 18 patients (50%) who received ΌΙ17Ε6 (ΕΜΌ 525797) at a dose of 500 mg or higher, no progression of the disease was detected by radiography for 16 weeks or longer. In two patients, long-term treatment with ΌΙ17Ε6 (ΕΜΌ 525797) at a dose of 500 mg is associated with a significant decrease in PSA levels and a clinical improvement in terms of pain reduction. At least one patient also had a reduction in the primary tumor and normalization of the size of the treated lymph node. Thus, it turns out that ΌΙ17Ε6 (ΕΜΌ 525797) is active as a single agent in at least some patients with late-stage mSCTD.

As a result, it was found that ΕΜΌ 525797, administered as a single agent in single and multiple doses, is well tolerated by patients with tSCRS with bone metastases and progressive disease after preliminary chemotherapy without spontaneous remissions. It is not possible to establish any safety risks, and there is preliminary evidence of clinical success in many patients. Due to its targeted action and safety parameters, ΌΙ17Ε6 (ΕΜΌ 525797) is a promising combination therapy.

In sum, the invention is directed to the following:

the use of antibodies No. 17-6 to integrin-ay or a biologically active variant thereof, or their modification for treating patients or for the manufacture of a medicament for treating patients, said patients suffering from prostate cancer, preferably castration-resistant prostate cancer (SCRS), where preferably said SCRS is accompanied by high serum PSA levels in the range of 25 to 10,000 ng / ml, more specifically levels of more than 25 ng / ml, or more than 50 ng / ml, or more than 1000 ng / ml, or more than 250 ng / ml, or more than 500 ng / ml or more than 1000 ng / ml, or more than 2500 ng / ml, or more than 5000 ng / ml, or more than 7500 ng / ml.

The appropriate use of antibodies is ΌΙ17Ε6, where the cancer metastasizes, mainly in the tissues of the bones and / or lymph nodes.

The appropriate use of antibodies is ΌΙ17Ε6, where the level of the prostate-specific antigen (PSA) during treatment decreases by more than 5, 10, 20 times, preferably 10 times compared with the level before treatment with antibodies.

The appropriate use of antibodies is ΌΙ17Ε6, where a decrease in PSA level is achieved after 4-8 months of treatment, preferably after 4 months, more preferably after 6 months.

Corresponding use of antibodies is ΌΙ17Ε6, where during the course of treatment with antibodies the number of circulating tumor cells is reduced (ssi1ypd (total se1k, STS).

Appropriate use of antibodies ΌΙ17Ε6 for a patient with SCRS who has removed the prostate or, alternatively, who received radiation therapy.

Appropriate use of antibodies ΌΙ17Ε6 to reduce the pain observed in prostate cancer, preferably with SCRS, preferably accompanied by bone metastases.

Appropriate use of antibodies ΌΙ17Ε6, where the patient has previously received chemotherapeutic and / or hormonal agents, preferably when the cancer progresses after said preliminary treatment with chemotherapeutic and / or hormonal agents.

The appropriate use of antibodies is ΌΙ17Ε6, where the effective dose of antibodies is 500-1500 mg every 2 weeks, preferably 500-1000 mg every 2 weeks or 1000-2000 mg per month.

The appropriate use of antibodies is ΌΙ17Ε6, where an effective dose of 500-1000 mg is administered in a single infusion.

The appropriate use of antibodies is ΌΙ17Ε6, where the antibodies are administered in the course of monotherapy without the use of additional chemotherapeutic agents.

The appropriate use of antibodies is ΌΙ17Ε6, where the antibodies are administered in a combination formulation with a cytotoxic / cytostatic or hormonal agent, sequentially or simultaneously.

The corresponding use of antibodies is ΌΙ17Ε6, where in the indicated combination prescription the cytostatic or cytotoxic agent is selected from the group consisting of a chemotherapeutic agent, radiation, tyrosine kinase inhibitor and angiogenesis inhibitor, wherein said tyrosine kinase inhibitor is an anti-ΕγΒΒ antibody selected from the group consisting of from antibodies to ΕΟΡΚ, antibodies to Neg2 and antibodies to Neg3, and the indicated angiogenesis inhibitor is an inhibitor of the inhibitor

- 4,032,117 alpha-ν, preferably peptide ΒΟΏ, preferably cylengitide.

The corresponding use of antibodies is ΌΙ17Ε6, where the biologically active variant or modification contains sections of CMEA and variable regions of light chains, which are 80-95% identical in amino acid sequence to variable regions of ΌΙ17Ε6.

The corresponding use of antibodies is ΌΙ17Ε6, where the biologically active variant or modification contains a constant region that is at least 80-98% identical in amino acid sequence to the constant region ΌΙ17ΌΙ6.

Appropriate use of antibodies ΌΙ17Ε6 containing one or more modifications with regions of the reading frame of the heavy chain:

ΕΈ1: OUOOOOZAEELERZAZUKMZSKAZBUTGZ (ZEO Ιϋ Νο. 16)

ΕΉ2: SEARCH <2CREOSYE1C (3Εβ THAT Νο. 17)

REZ: KATMTAAOZZZTAUMOZSZTZEOZAUUUSAZ (ZEO 13 Νο. 18)

EP 4: ISOSTZUTUZ (ZEO TO 19ο. 19), where one or more of the bold or underlined amino acids are mutated and differ from the amino acids in the corresponding initial sequence.

The corresponding use of modified antibodies ΌΙ17Ε6 containing a constant region of human Ι§Ο1 instead of the region of human ΙβΟ2 or a hinge region of human ΙβΟ2 instead of the hinge region of human Ι§Ο1.

A method of treating a patient who is resistant to castration of prostate cancer (SVRS), preferably accompanied by bone metastases, comprising administering antibodies ΌΙ17Ε6 to integrin αν or a biologically active variant thereof or modifying them at a dose of 500-1000 mg every two weeks, preferably for a period of at least 3 months.

A method for reducing in a patient suffering from prostate cancer, preferably castration-resistant prostate cancer (SVRS), a pathologically elevated serum PSA level of more than 5 times, preferably more than 10 times, by administering the indicated patient hybrid monoclonal antibodies ΌΙ17 in an effective dose of at least 500 mg every two weeks or at least 1000 mg per month, with a pathologically elevated serum PSA level before antibody treatment of at least 25 ng / ml, preferably at least 50 ng / m .

A suitable method is where the cancer metastasizes to the tissue of the bones and / or lymph nodes.

Brief Description of Drawings

FIG. 1 shows a table summarizing the results of measuring the number of circulating tumor cells (CTCs) in 6 patients with SVRS at a dose level of (1) 250 mg, (2) 500 mg, and (3) 1000 mg. The days of treatment are indicated along the X axis, the number of circulating tumor cells (CTC) is indicated along the Υ axis;

FIG. 2 shows a dose-dependent pharmacokinetic profile of ΌΙ17Ε6 (ΕΜΌ 525797) for doses of antibodies of 250, 500, 1000 and 1500 mg, administered every 4 weeks. On the X axis, the period after the first infusion (h) is indicated, on the оси axis, the serum concentration (μg / ml) is indicated;

FIG. 3 shows the duration of treatment for ΌΙ17Ε6 group of patients with SVRS. On the X axis: the duration of treatment (weeks), on the оси axis: dosage levels (level 1 - 250 mg, level 2 - 500 mg, level 3 1000 mg, level 4 - 1500 mg);

FIG. 4A shows a change in PSA level (ng / ml serum) during treatment of ΌΙ17Ε6 of a particular patient with SVRS (No. 2001) without prostatectomy, with bone metastases (treatment was started on 08.24.2009). The X-axis indicates the duration of treatment (days), the оси axis indicates the level of PSA (ng / ml);

FIG. 4B shows the average parameter of pain interference in the same patient as in (A). The X-axis indicates the duration of treatment (days), the оси axis shows the average indicator of pain interference;

FIG. 5A shows the progression of PSA levels during treatment of ΌΙ17Ε6 in a second patient with SVRS with progressive disease after chemotherapy and prostatectomy, with bone metastases. The X-axis indicates the duration of treatment (days), the оси axis indicates the level of PSA (ng / ml);

FIG. 5 (B) shows the average parameter of pain interference in the same patient as in (A). The X-axis indicates the duration of treatment (days), the оси axis shows the average indicator of pain interference;

FIG. 6 shows the results of scanning (computed tomography) of a patient from the group with a dosage of 500 mg, indicating a significant reduction in the size of the primary tumor; (a) before treatment ΌΙ17Ε6, (b) after the 17th administration of ΌΙ17Ε6 (after 4 months);

FIG. 7 shows the ratio of bone markers / circulating bone markers after treatment ΌΙ17Ε6; 1 - dosage level 1, 2 - dosage level 2.

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DETAILED DESCRIPTION OF THE INVENTION

ΌΙ17Ε6 are 1dC2 hybrid monoclonal antibodies designed according to a specific plan and aimed at integrin alpha-ν (receptor). Therapy of cancer with the help of these antibodies reduces the side effects associated with this type of therapy, especially immune responses, thus reducing immunogenicity. These antibodies are described in detail in patent document AO 2009/010290.

Their hypervariable regions (CEJ) originate from murine monoclonal antibodies MAB 17–6 (M73034). These initial murine antibodies IgC1 'are described, for example, in the work of My) ap8 c1 a1. (1995; TCc11 8c1. 108, 2825) and patents I8 5985278 and EP 719859. Mouse monoclonal antibodies TAB 17-6 were produced by the hybrid cell line 272-17E6 and registered under accession number 88 ACC2160.

The domains of their light chains originate from their humanized (1 pc) monoclonal antibody 425 to the epithelial growth factor receptor (Ε6ΕΚ.) (Matuzumab). These antibodies are described in detail, for example, in patent document EP 0531472 B1 and originate from their murine progenitor 425 (murine antibodies MAB 425, ATCC HB9629). These antibodies were obtained for the human A431 carcinoma cell line and bind to a polypeptide epitope on the external domain of the human epithelial growth factor receptor (ΕΟΕΚ), as was discovered. In clinical studies, it was found that matuzumab is highly effective.

ΌΙ17Ε6, as used according to the present invention, mainly comprises:

(ί) SEC section. light and heavy chain derived from murine monoclonal antibodies 17E6 to integrin αν, (ίί) region of the reading frame of the light chain, which is taken from humanized monoclonal antibodies 425 to ΕΟΕΡ., (ίίί) reading frame of the heavy chain obtained from murine monoclonal antibodies 17E6 to integrin αν, optionally containing one or more amino acid mutations at specific positions, and (ίν) the constant region of the heavy chain originating from human 1dC2, and the constant region of the light chain of the human kappa, where in the indicated domain is hinged the 1dC2 region has been replaced by the hinge region of the human 1dC1 and where, at the discretion, one or more mutations in 1dC2 have been made.

Specifically, ΌΙ17Ε6 (designated ΌΙ-17Ε6Υ21ι (Ν297Ο) or ΕΜΌ 525797), as used for treatment in accordance with the application and in clinical trials, as described above and below, have the following amino acid sequence:

(ί) variable and constant sequences of the light chain (8ΕΟ ΙΌ ΝΟ: 1) ριομτοβ рιузазузузузузазркркркреререререререререререререререскререререререререυυυυυυυυυυυυυυυυυυυυυυυυυυυзз

OTRZKEZSZBZbTRUTGTTZZORORETATUUseyTRRUTGbWOKTUKTUKTUAA

P 3UEIER P5RE <2K5STA5UUSYS®1 ΕΥ RAKEACUTS KURYAJ <2 Ξ6Ν33Ε3 UT E <2

P8KR8TUZE83TZKAREKNUAUESEUTNT <2SE88RUTKZEPV.6ES AND (ίί) variable and constant sequences of the heavy chain (8ΕΟ ΙΌ ΝΟ: 2) DUSEDOZEEKREAZUKUBSTBUTEZGBMUNGNM

KZSUTEUMETGKRKATMTTRTZTZTAUMEZZKERTAUUUSAZZGakaama

Иб ^ бТТУТУЗЗЗЗТК6Р 3V Е РАРАРЗЗ КЗТ 3 Е ЗТААССЬУКРУ Е Р Е РУЗУЗКИ 36

ALTZBUNTGRAUEOZBUZZZUUTURZZKEBTOTUTUTSYURNKRZMTKURKTU

ERKZOKTNTSRRSRARRUA6RZUEEGRRKRKTRM13KTREUTSUUURUZNERRE

U0EYIUUR6UEUNYAKTKRV.EESA08TEEUUZUTUUN <2RTSI6KEUKSKUZ TsKSERAR1EKT18KTKS0RKERaUUTRRZEEEMT№SUZTSUKeEUR8R1AUE IE 8Ν6ΟΡΕΝΝΥΚΤΤ RRMRZ RS8 E EUZ KTUOK8E.VD <26IUEZS 3UMNEAEN YNUTOKZZEZRbK where the underlined sequences represent the variable regions with Say (bold regions of identity with the parental murine antibodies). The modified hinge section of CS1 is represented by the sequence ΕΡΚ88 ^ ΚΤΗΤСΡΡСΡ (8ΕΟ ΙΌ ΝΟ: 3), and Ap is the substitution in the domain of Ι§Ο2.

However, as shown in AO 2009/010290, variants ΌΙ17Ε6 may also be used according to the provisions of this invention. So, in the described treatment of patients with prostate cancer, variants ΌΙ17Ε6 can be used, containing one or more modifications in the sections of the reading frame of the heavy chain

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ГК1: ОУОС ^ ЗСАЕЛЛЕРСАЗУВМЗСКАЗЗУТГЗ (ЗЕ <2 Ю Νο. 16)

EB2: IUK0KR33 <2SIEI1S (5E <2 Yu Νο. 17)

GKZ: KATMTAAOZZZTAUMSZSZTZEOZAUUUSAZ (Zeo Yu ΝΟ. 13)

EB4: IefbTZuTUZZ (WEU Yu Ko. 19), where one or more provisions are mutated, which are underlined and in bold.

In more detail, the heavy chain reading frame region can be mutated in one position, several positions, or in all positions from the following positions: A9, E13, M20, K38, K40, A72, 876, 082. 085, T87, 891, and 8113. These variants exhibit the same or very close biological activity and efficacy as ΌΙ17Ε6 defined above by their sequences.

In General, the invention, as described, also includes modifications and variants of antibodies ΌΙ17Ε6, which are functionally and / or pharmaceutically identical or similar to unmodified ΌΙ17Ε6 and where sections of SEC and variable sections of the heavy and light chains of at least 80% or at least 85 %, or at least 90%, or at least 95% are identical in their amino acid sequence to the corresponding variable regions ΌΙ17Ε6. In addition, the invention also includes modifications and variants of antibodies ΌΙ17Ε6, which are functionally and / or pharmaceutically identical or similar to unmodified ΌΙ17Ε6, and where the constant regions are at least 80% or at least 85%, or at least 90%, or at least 98% identical in their amino acid sequence to the corresponding constant regions ΌΙ17Ε6. Changes in the constant regions of the Ι§0 antibody chains can improve specific properties, such as immunogenicity, LISS, etc.

In a further aspect, antibodies ΌΙ17Ε6, as used according to the invention, can be fused to a cytotoxic agent, preferably a cytokine, such as ΙΕ2, ΙΕ8, ΙΕΝβ, ΙΕΝα, ΤΝΡα, 0M-C8E, 0-C8E, or such as indicated below. A cytokine can be attached at its Ν-terminus to the C-terminus of the antibody heavy chains or at its C-terminus to the Ν-terminus of the antibody heavy and light chains.

According to the present invention, antibodies ΌΙ17Ε6 are highly effective in patients suffering from prostate cancer, especially in patients whose tumor progresses after chemotherapy and / or hormone therapy and / or prostate surgery, such as prostatectomy.

To enhance the activity or prolong the effectiveness of ΌΙ17Ε6 or their described modifications, combination therapy in combination with cytotoxic or cytostatic agents can be used. A cytotoxic or cytostatic agent can be administered with antibodies sequentially or simultaneously in doses generally accepted and convenient in the clinical treatment of cancer. Preferred cytotoxic / cytostatic agents according to the present invention are anti-angiogenic agents, described in more detail below, anti-HIV or anti-Neg3 agents, including the corresponding antibodies, such as Neheerb® (trastuzumab, Gtayigit®), ΕγΝΙιιχ® (cetuximab, e1x1tb) or panitumumab (rapiyitit). In a preferred embodiment, the combination therapy of antibodies No. 17-6 together with cetuximab is effective against prostate cancer, especially with SCRS, according to the present invention.

For the same purpose, ΌΙ17Ε6 can be entered together (sequentially or simultaneously) with hormonal drugs according to known prescriptions.

The term castration-resistant, as used here, refers to prostate cancer status, where the disease progresses while keeping testosterone levels lower than those of castrate, which is usually less than 50 ng / 100 ml. This term is used as a synonym for hormone-resistant, or hormone-insensitive, or androgen independent.

The term indicator of pain interference (general) means the registration of pain as a result of a disease that manifests itself during the administration of an effective medication. Interference caused by pain is assessed on the basis of VpeG Rush Bragging (ΒΡΙ). ΒΡΙ is used to assess pain interference in: (a) general activity, (b) mood, (c) ability to walk, (b) normal work, (f) relationships with other people, (D) sleep and (e) pleasure from of life. The total indicator of pain interference is calculated as: (average indicator of questions with the answer received) x (7 / number of questions with the answer received). If 4 or more questions remain unanswered, the overall pain interference score is set as absent.

The term cytotoxic agent, as used here, refers to a substance that inhibits or prevents the functioning of cells, causing cell destruction. The term is intended to include radioactive isotopes, chemotherapeutic agents and toxins, such as enzymatically active toxins of bacterial, fungal, plant or animal origin, or fragments thereof. The term may also include representatives of the cytokine family, preferably ΙΕΝγ, as well as antitumor agents that also have cytotoxic activity.

The term cytotoxic agent, as used here, refers to a substance that inhibits or inhibits the growth and reproduction of cells without destroying the cells.

- 7 032117

The term cytokine is a generic term for proteins released by one population of cells that act on other cells as intercellular mediators. Examples of such cytokines are lymphokines, monokines, and traditional peptide hormones. Cytokines include growth hormones such as human growth hormone, Ν-methionylated human growth hormone and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle-stimulating hormone (FSH, Ρ8Η), thyroid-stimulating hormone (T8H) and luteinizing hormone (LH); liver growth factor; fibroblast growth factor; prolactin; placental lactogen; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor (VARIUM); integrin; thrombopoietin (TPO); nerve growth factors such as ΝΟΡβ; platelet growth factor; transforming growth factors (TOR), such as TOR and ΤΟΡβ; erythropoietin (EPO); interferons such as ΙΡΝα, ΙΡΝβ and ΙΡΝγ; colony stimulating factors such as Μ-Ο8Ρ, OM-ΟδΡ and O-ΟδΡ; interleukins, such as 1B-1, 1b-1a, 1b-2, 1b-3, 1b-4, 1b-5, 1b-6, 1b-7, 1b-8, GE-9, GB-10, GB- 11, GB-12 and ΤΝΡα or ΤΝΡβ. Preferred cytokines according to the present invention are interferons and ΤΝΡα.

The term anti-angiogenic agent refers to a natural or synthetic compound that blocks the development of blood vessels or prevents it to some extent. An anti-angiogenic molecule may, for example, be a biological molecule that binds to and blocks an angiogenic growth factor or receptor for a growth factor. Here, a preferred anti-angiogenic molecule binds to a receptor, preferably an integrin receptor or ΥΕΟΡ receptor. The term also includes, according to the present invention, integrin (receptor) inhibitors.

The term integrin inhibitors or integrin receptor inhibitors refers to a natural or synthetic molecule that blocks and inhibits integrin receptors. In some cases, the term includes antagonists targeting the ligands of these integrin receptors (such as for α _ν β ₃ receptors: vitronectin, fibrin, fibrinogen, von Willebrand factor, thrombospondin, laminin; for α _ν β ₅ : vitronectin; for α ,, βη : fibronectin and vitronectin; for α _ν β ₆ : fibronectin). Antagonists targeting integrin receptors are preferred according to the present invention. Integrin (receptor) antagonists can be natural or synthetic peptides, non-peptides, peptidomimetics, immunoglobulins, globins, such as antibodies or their functional fragments, or immunoconjugates (fusion, fusion proteins). Preferred integrin inhibitors target the integrin receptor α _ν (e.g., α. _Ν β _3. Α ,, β _5. Α _ν β ₆ and their subclasses). Preferred integrin inhibitors are α _ν antagonists and in particular α _ν β ₃ antagonists. Preferred α _ν antagonists according to the invention are IOI peptides, peptidomimetic antagonists (non-peptide) and antibodies to integrin receptors, such as antibodies that block α _ν receptors. Examples of non-immunological antagonists of α _ν β _{3 are} described in patent claims I8 5753230 and I8 5766591. Preferred antagonists are linear and cyclic BBC-containing peptides. Cyclic peptides are generally more stable and have longer serum half-lives. However, the most preferred integrin antagonist of the present invention is cyclo (Lgd-O1u-L8p-PRie-PMeUa1) (No. 121974, Syepdy1be®, Megsk Kdal, Oegtapu; EP 0770 622), which effectively blocks integrin receptors α _ν β ₃ , α _ν βι, α _ν β ₆ , α _ν β ₈ , α. _{|| 3} , β ₃ . According to the present invention, combination therapy ΌΙ17Ε6 together with SyepdyGbe is effective in patients with prostate cancer and preferably with SIRS.

According to the understanding of the present invention, a chemotherapeutic agent or antitumor agent is considered to be a representative of the class of cytotoxic agents as defined above, and includes chemical agents that exhibit an antitumor effect, i.e., prevent the development, maturation or spread of tumor cells and are directed directly to tumor cells or act indirectly by mechanisms such as modification of a biological reaction. Suitable chemotherapeutic agents according to the present invention are preferably natural or synthetic chemical compounds, but biological molecules such as proteins, polypeptides, etc., are not expressly excluded. On the market, at the stage of clinical evaluation and preclinical development, there are a large number of antitumor agents that should not be excluded in the present invention for the treatment of tumors / neoplasias with combination therapy using ΤΝΡα and antiangiogenic agents, as mentioned above. It should be noted that chemotherapeutic agents can be administered at the discretion along with the above antibody-based drug. Examples of chemotherapeutic agents include alkylating agents, for example, nitrogen derivatives of mustard gas, ethyleneimine compounds, alkyl sulfonates and other compounds with an alkylating effect, such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example folic acid, purine or pyrimidine antagonists, mitosis inhibitors, for example, vinca alkaloids and podophyllotoxin derivatives; cytotoxic antibiotics and camptothecin derivatives. Preferred chemotherapeutic agents or chemotherapy types include amifostine (etiol), cabaxitacel, cisplatin, dacarbazine (ΌΤΙΟ), dactinomycin, docetaxel, mechlore

- 8 032117 tamine, streptozocin, cyclophosphamide, carnustine (ALL), lomustine (SSII), doxorubicin (adriamycin), lipo-doxorubicin (daunoxom), procarbazine, ketoconazole, mitomycin, sitarabin, 5-etocid, 5-etocid, 5-etocis, 5-etocid, 5-etocid, 5-etocid, 5-etocid, 5-etocid, 5-etocid, 5-etocis-5, 5 ), vinblastine, vincristine, bleomycin, paclitaxel (taxol), docetaxel (taxotere), aldesleukin, asparaginase, bisulfan, carboplatin, cladribine, camptothecin, CPT-11, 10-hydroxy-7-ethyl camptothecin (§N38), dacarbaz phloxuridine, fludarabine, oxyurea, ifosfamide, idarubicin, mesna, interferon-alpha, interferon-beta, irinotecan, mit ksantron, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargazu, pentostatin, pipobroman, plicamycin, streptozocin, tamoxifen, teniposide, testolactone, thioguanine, tiotera, uracil mustard (IGASOM shiChagb). vinorelbine, chloambucil and their combinations. The most preferred chemotherapeutic agents of the present invention in combination with ΌΙ17Ε6 are carbazitaxel, cisplatin, docetaxel, gemcitabine, doxorubicin, paclitaxel (taxol), irinotecan and bleomycin.

ΌΙ17Ε6 is usually administered by intravenous injection, but other forms of administration suitable in the art for drugs with antibodies / proteins are also applicable. All standard infusion solutions and formulations are applicable, such as those described in AO 2005/077414 or AO 2003/053465, including liposome formulations. In addition, it is convenient to produce nanoparticles from human serum albumin loaded with ΌΙ17Ε6 and chemotherapeutic drugs at their discretion (to increase cytotoxicity) (Vyutaepak 2010, 8, 2388-98; Aadpeg s1 a1.).

The following examples describe the invention in more detail, but do not limit the invention and its scope, as described in the claims.

Examples

Example 1. The construction of the study.

Phase I of the study was started to determine the safety, pharmacokinetics, and antitumor activity of ΌΙ17Ε6 in treated patients with SIRS, including actions on prostate-specific antigen, circulating tumor cells (CTCs), and metastases in soft tissues and bones. All patients suffered from a progressive disease after chemotherapy. Patients received intravenous infusion of 250, 500, 1000, or 1500 mg ΌΙ17Ε6 for 1 hour.

Suitable patients were 18 years of age or older and had histologically or cytologically confirmed prostate cancer with evidence of bone metastases after prior chemotherapy. The patients either underwent an orchiectomy, or they received long-term treatment with androgen off using an agonist or antagonist of a gonadotropin-releasing hormone, and antiandrogen therapy was discontinued at least 4 weeks prior to listing.

It was required that patients undergo continuous (i.e., at least 3 months) therapy with continuous administration of bisphosphonate or be without any bisphosphonate therapy, with a total serum testosterone level of less than 50 ng / dl. All patients had signs of progressive disease, defined as at least two prostate-specific antigen (PSA) levels above the individual lowest level with a minimum increase of 10% for each, determined at least two weeks before screening; for inclusion in the list, regardless of the level of PSA, there was enough progression (tumor) in the nodes or viscerally. In addition, patients should have had a coefficient from 0 to 2 on the basis of the Baet SooregBue Opso1od Ogoir (ESOC) count, life expectancy of at least 3 months, and adequate hematology, kidney, and liver functions. In each research center, the Institute Supervisory Board approved a research protocol, and all patients had to provide written consent with the information received.

In this phase 1 of the study of the effect of increasing the dose in several centers with open encryption, patients with tsIRS received 3 intravenous infusions ΕΜΌ 525797 in doses of 250, 500, 1000 or 1500 mg, administered for 1 hour every 2 weeks until the reaction is recorded at the end of 6 weeks. Patients without evidence of disease progression were suitable to receive further doses every two weeks until disease progression or manifestation of unacceptable toxicity. For the first 6 weeks, dose-limiting toxicity (ORT) was evaluated and within 4 weeks after the last administration, ΕΜΌ 525797 patients were monitored for safety assessment. Patients were divided into 4 groups with a consistent increase in dose; after the last of the 6 patients in the group with the given dose reached the end of the 6th week, the Safety Control Committee (§aGe1u Mopioppd Sottiye) determined the subsequent dose increase.

The list included 26 male patients aged 43 to 80 years (average age 66 years), they received at least one intravenous infusion ΕΜΌ 525797, making up the safety population. All patients were white. In general, the demographic characteristics in the 4 groups by dose were comparable (Table 1a), the average time after the first diagnosis was 5.2 years (range from 2 to 18 years), and the average time from diagnosis to the first metastatic stage of the disease was 0, 1 year (range 0-16 years).

- 9 032117

Two patients were withdrawn from the study before the end of the E-T period and were then replaced, 24 patients received 3 doses of 525797 during the treatment until week 6.

Table 1a Initial Patient Demographics (Safety Test Population)

Stick character Groups with a dose of ΟΙ17Ε6 (EME 525797) Total (Ν = 26) 250 mg (N = 8) 500 mg (N = 6) II about II O 5 '< ~ 1 Average age (range), years 67 (57-78) 63 (47-77) 62 (43-79) 66 (52-80) 65 (43-80) Average weight 82,2 85.8 80.5 93.7 85.3 Average BMI, kg / m ² 26.2 28.1 26.0 28.9 27.2 Stage (tumor, nodes, metastases) with a diagnosis, l (%) II 1 (12.5) 3 (50.0) 0 1 (16.7) 5 (19.2) III 2 (25.0) 1 (16.7) 0 1 (16.7) 4 (15.4) IV 5 (62.5) 2 (33.3) 5 (83.3) 2 (33.3) 14 (53.8) Lack of 0 0 1 (16.7) 2 (33.3) 3 (11.5) Previous anticancer therapy, η (%) Hormone therapy 8 (100) 6 (100) 5 (83.3) 6 (100) 25 (96.2) Immunotherapy 1 (12.5) 0 0 0 1 (3.8) Radiotherapy 7 (87.5) 3 (50.0) 3 (50.0) 4 (66.7) 17 (65.4) Chemotherapy 8 (100) 6 (100) 6 (100) 6 (100) 26 (100) Surgery 6 (75) 2 (33.3) 3 (50.0) 2 (33.3) 13 (50.0)

BMI - body mass index.

Table 1b

Summary data

Tasks • Safety, tolerability and pharmacokinetics after several intravenous doses of increasing doses • Determination of changes in markers of bone metabolism during exposure • Study of changes in efficacy parameters within the entire dose range • Identification of potential pharmacodynamic markers Population of individuals Individuals with prostate cancer with evidence of bone metastases after prior chemotherapy with, for example, taxane or mitoxantrone The number of individuals For each dose level n = 6 Dose selection 250, 500, 1000, 1500 mg by intravenous infusion for 1 h Exposure duration 6 weeks (after a week) and 4 weeks of observation Decision-making on the continuation of exposure in the absence of progression in the patient Dose increase Dose increase based on toxicity score (O1.T} after 6 weeks

Clinical trial phase была was carried out in 3 centers in Germany and one center in Belgium. The results revealed the biological activity of a single agent in individuals with castration-resistant prostate cancer with bone metastases and a progressive disease after chemotherapy.

Example 2. The duration of treatment.

the patient (age 43-80 years) received 3 doses (weeks 1, 3 and 5) before evaluating the response at the end of week 6. Patients without disease progression could continue to receive additional doses every 2 weeks. At the end of the first 6 weeks, dose-limiting toxicity was assessed (boke-NTBTD ΙοχίοίΙν, OTT), and patient follow-up to determine safety continued for another 4 weeks after the last administration of ΌΙ17Ε6.

In the table. 2 summarizes the data on the duration of the course for patients in each group. The average duration of the course ΕΜΌ 525797 for patients was 117.5 days (mean value 74.5 days,

- 10 032117 range 14-534 days). Of the 24 patients in 13, the duration of the course was longer than expected (> 84 days), and in 2 patients from the 500 mg group, treatment continued for 297 and 534 days, and in one of the patients in the 1000 mg group, treatment was carried out for 310 days. During the observation period of EBT (6 weeks) no signs of EBT were observed. All patients had at least one drug-related effect (TEMA) and no dose dependence was observed in TEMA.

+ continued treatment;

* excluded patients (only 1st and 2nd infusion).

The study protocol established that individuals should receive at least 3 doses (250, 500, 1000 mg every 2 weeks) )7Ε6 after a week and that individuals without evidence of a progressive disease should receive further therapeutic doses after a week.

The duration of treatment in all 4 groups (beginning - August 2010). In group 2 with a dose of 500 mg every 2 weeks in two patients (2001 and 2002) at a late stage (estimated mean TO 8 <12 months), an unexpected tumor response to treatment was observed for more than 10 months.

In the table. 2b shows the duration of exposure (as of August 2010). Dose level 1: 250 mg ΌΠ7Ε6; dose level 2: 500 mg ΌΠ7Ε6; dose level 3: 1000 mg ΌΠ7Ε6; dose level 4: 1500 mg ΌΠ7Ε6

Table 2b

In the table. 3 summarizes the indicators of the dependence of the parameters TEAE on the dose. 11 patients (42.3%) showed dose-dependent TEAEs, which are most often observed in the classes of system organs. Lesions of the skin and subcutaneous tissues (4 patients in general; generalized itching, redness of the skin, rash), General disorders and painful conditions at the injection site (3 patients in total; trauma, inflammation of the mucous membrane, peripheral edema), Gastrointestinal disorders (2 patients in total; dry mouth, swelling of the tongue, upper gastrointestinal hemorrhage) and Infections and infestations (2 patients in total; rhinitis, sepsis). Only two patients (7.7%) had dose-dependent TEAEs of degree 3 or 4: one patient in the 500 mg group had a degree 3 increase in gamma-glutamintransferase (COT) level and one patient in the 1000 mg group had sepsis 3 degree.

Two patients had severe TEAEs that were considered associated with exposure. These were grade 1 bleeding in the upper gastrointestinal tract in a patient in the 250 mg group and grade 3 sepsis in one patient in the 1000 mg group. On examination, this last patient was diagnosed with persistent urinary tract infection and recurring sepsis, of which the last event was considered to be related to ΌΠ7Ε6 (ΕΜΌ 525797). Four patients died, and the researchers concluded that there was no causal relationship between all of these deaths with ΕΜΌ 525797.

- 11 032117

In 6 patients (23.1%), exposure was constantly interrupted due to the detection of TEAE, including 4 patients in the 250 mg group (bleeding in the upper gastrointestinal tract on day 12, muscle weakness on day 53, paralysis on 46- day and blockage of the ureters on the 30th day) and one patient in the 500 mg groups (increase in grade 3 COT on the 534th day) and 1500 mg (metastases in the central nervous system on the 85th day). No skin reactions at the injection site were noted. Eight patients showed toxic shifts to the 3rd and 4th degree relative to the initial examination in hematology and biochemistry. However, there were no obvious trends in laboratory analyzes, vital signs, and ECG data. Overall, 65.4% of patients had the same worst indicators of status status upon exposure compared to baseline.

Table 3

Emerging Side Effects Associated with Drug Administration (TEAE)

TEAE related to EMO 525797 η (%) Adverse Event Patients 11 (42) Lesions of the skin and subcutaneous tissue 4 (15) Generalized itching 2 (8) Skin redness 1 (4) Rash 14) General disorders and painful conditions at the injection site 3 (12) Injury 14) Mucosal inflammation 14) Peripheral edema 14) Gastrointestinal Disorders 2 (8) Dry mouth 14) Swelling of the tongue 14) Gastrointestinal hemorrhage 14) Infections and infestations 2 (8) Rhinitis 14) Sepsis ¹ 14) Visual impairment 14) Blurred vision 14) Survey 14) High blood pressure 14) Musculoskeletal and connective tissue disorders 14) Joint pain 14) Nervous system disorders 14) Dysgeusia 14) Disorders of the respiratory system, chest and mediastinum 14) Dyspnea 14)

* According to the classification of MESA of primary organ systems. Preferred version of MESJA Wegzyup 13.0;

ΐ Stage 3 was observed after the first 6 weeks (period for determining dose-limiting toxicity).

Examples of observed side effects.

(ί) In a 62-year-old man 13 days after the first and only infusion of ΌΙ17Ε6 (250 mg), grade 1 bleeding was observed in the upper part of the gastrointestinal tract. The individual was found to have a slight bloody vomit and was hospitalized. Gastroscopy revealed an ulcer in the distal esophagus. Active bleeding was stopped, omeprazole treatment was performed, and the phenomenon stopped.

(i) A 79-year-old patient, 1 day after the most recent infusion and 9 weeks after the first infusion of ΌΙ17Ε6 ^ ME 525797) (1000 mg), developed sepsis (grade 2) due to E. Gayesayh infection. The patient was hospitalized and discharged after recovery. A month later, the patient had a second episode of sepsis (3rd degree) again due to E. Gaes1sch, 4 days after the last infusion and 2.5 months after the first infusion. The patient was hospitalized and discharged after treatment. A month later, the patient had a third episode of sepsis (grade 3) 4 days after the very last and 3.5 months after the first infusion, which was attributed to the action of ΕΜ ^ 525797.

Summary.

Safety data was analyzed for all four 8MS groups.

In general, no cases of MBT were observed. The researcher and / or sponsor considered that the observed MBT is identified as any hematologic or non-hematologic toxicity of degree 3 or 4, is causally related to the test product, but not to allergy / hypersensitivity reactions and not to any extra-laboratory parameters, does not correlate with clinical parameters that are reversible within 7 days.

To date, MTE has not been achieved (maximum tolerated doses).

Only 2 8ΑΕ associated with the study drug was observed.

- 12 032117

Example 4. Pharmacokinetics and pharmacodynamics.

After single and multiple doses of ΕΜΌ 525797, a dose-dependent, non-linear pharmacokinetics profile was observed (Fig. 2). After the first 1-hour intravenous infusion, C _max ΌΙ17Ε6 (ΕΜΌ 525797) was achieved within 1-2 hours after the start of the dose. The time of half-disappearance increased with the dose due to the fact that the excretion of ΕΜΌ 525797 increases with increasing dose, while the average volume of distribution remains constant for the entire dose range (Table 4).

As shown in FIG. 2 (Table 4), with the introduction of 500 mg of the drug every 2 weeks, patients with SIRS in group 2 achieved a serum level of 1C ₉₅ , while this did not happen in patients in group 1 with 250 mg every 2 weeks. The concentration in the total serum of ΕΜΌ 525797 in group 2 with the introduction of 500 mg every 2 weeks was higher than 1C ₉₅ and reached 1C _{99 in a} non-linear manner, whereas this did not occur in the group with the administration of 250 mg every 2 weeks.

Table 4

250 mg (N = 6) 500 mg (N = 6) 1000 mg (N = 6) 1500 mg (N = 6) Average Stax ± 30 μg / ml 57.1 ± 13.8 131.9 ± 22.8 376.6 ± 64.1 498.8 ± 132.8 Average T _max (range), h 1 (1-5) 3 (1-5) 1 (1-4) 1 (1-8) Average C ,,. ,,, ± 3ϋ, μg / ml 2.7 ± 4.1 28.0 ± 12.3 102.8 ± 28.2 150.7 ± 47.4 Average ν _Μ ± 80, l 4.7511.19 4.35 ± 0.17 3.36 ± 0.36 4.46 ± 1.22 Average AuSt · ± 3ϋ, μg / ml h 6694 ± 3746 21225 ± 6505 68145 ± 12811 87535 ± 21575 Ratio AiS, mean ± 3ϋ 1.42 ± 0.46 1.37 ± 0.39 1.70 ± 0.36 1.70 ± 0.18 The ratio_Sp, ah 'average ± 30 1.11 ± 0.17 1.21 ± 0.22 1.25 ± 0.12 1.3310.18

AIS _t - the area under the curve of the concentration versus time within one full dosage interval;

With _max - the maximum concentration in serum; With _{t | P} - the minimum concentration in serum; ratio AiS - the relative area under the curve [AIS _t (dosage period 3) / AIS _t (dosage period 1)];

relation_C _tAX - relative maximum concentration in serum [C _max (dosage period 3) / C _max (dosage period 1)];

T _tah - time to achieve C _tax ·;

- the apparent volume of distribution in a stationary state.

After the administration of several doses of 1500 mg ΌΙ17Ε6 (ΕΜΌ 525797), the maximum serum concentrations and accumulation (exrocite) reached the maximum values of 1.33 and 1.70, respectively (dosage period 3 / dosage period 1) with a dose dependence.

In most patients, the concentration of circulating tumor cells (CTC) remained constant near the initial values (data not shown). Two patients, respectively, near the 14th and 42nd days after the start of treatment, there was a significant increase in the concentration of STS.

Antibodies to ΕΜΌ 525797 were found in 4 of 25 (16.0%) patients available for examination. All 4 patients were from the 250 mg group, 2 patients returned to a seronegative state after 2 weeks, there was no examination for one patient, one patient remained seropositive throughout the study period.

Example 5. Circulating tumor cells (CTC).

Estimation of the number of circulating tumor cells (CTCs) using Ce118eaaa was established by the Pharmacological Committee (Eob apb Egid At1shk1ga1yup) as a prognostic factor for patients with metastatic prostate cancer. Several groups have found that STSs are detected with high frequency in SIRS and their number correlates with the clinical picture (Be Vopo e! A1. 2008, Syp. Sapseg Kek., 8set e! A1. TPe Lapse! 2009).

In FIG. Figure 1 shows the effect of ΌΙ17Ε6 on circulating tumor cells (CTC). Patient No. 2002 from the group with a dose of 500 mg every 2 weeks showed a decrease in the number of STS. Other patients had an initially low level of STS, therefore, after 3 infusions by the 7th week, no significant changes were observed. This effect was absent in group 1 with the introduction of 250 mg every 2 weeks, where by the 7th week in 5 out of 7 patients there was a sharp rise (the number of STS).

Example 6. Bone markers.

Bone resorption is the leading cause of death in prostate cancer. In the progression of prostate cancer, processes in the skeleton are important. The study evaluated markers for assessing bone resorption and bone structure, pairwise correlation was determined for all markers in the group, and in

- 13 032117 group 2 there was a potential dose effect.

Bone markers are grouped together in group 2, but not in group 1. The biological meaning of this is not entirely clear, but this may indicate a dose-related effect on bone markers in the treatment of prostate cancer using ΌΙ -17Ε6. It is possible that ΌΙ -17Ε6 normalizes bone activity in such a way that bone resorption markers and bone structure markers are regulated more balanced, closer to the normal state than in a disease state. It has been found that with tSCRS, bone resorption markers are often overexpressed. The key biomarkers that can be observed in connection with the introduction of ΌΙ17Ε6 are ΆΌΆΜΤδ-1, 8TC1, W6 and W8.

As shown in FIG. 7, a comparison of two dosage levels (250 and 500 mg) was made. In the group with a dose of 500 mg, 3 clusters were revealed in pairwise correlation (right frame for dose level 2 = 500 mg).

Example 7. Changes in the level of PSA and the parameter of pain interference in the treatment of ΌΙ17Ε6.

In FIG. 4A and 5A show a change in serum PSA levels in two patients during treatment with 500 mg every 2 weeks ΌΙ17Ε6.

PSA levels are associated with tumor growth and positively correlate with tumor burden. It has been suggested that a decrease in PSA level of more than 50% compared with the initial level is a criterion for a biological response.

In clinical practice, PSA levels are measured easily and accurately. Most doctors base their decision to continue treatment on a general impression of the condition of the patients and on the kinetics of their PSA levels.

In two patients (see maps of individuals 2001 and 2002) from the group with a dose of 500 mg during treatment, a more than 8-fold decrease in PSA level was obtained compared to the initial values (Figs. 4A, 5A).

Table 5

PSA values in all individuals from the initial examination to the 7th week

a patient source νν161 νν3ά15 ν / 5829 »7843 1002 104.4 130.5 169.7 195.3 222 1004 5.7 5.9 11.3 8.7 6.6 1005 34.3 44.7 46.6 47 48.5 1006 1914 1622 1572 1531 1448 1001 60.1 68.1 88.9 123.9 167.2 1008 472 609.5 821.5 2001 77.5 83.3 81.5 129.6 111.3 2002 4774 6699 6500 5943 7878 2005 91.1 94.3 135.6 137.9 148.66 2007 28.9 25 33.3 40,4 2003 150,4 171.1 212.1 259.2 2009 1723 1788 2194 2694 3155 3003 83.00 84.40 102.60 108.50 109.50 3004 152.40 156.90 206.30 208.50 279.60 3001 354.80 450.50 539.60 528.00 3005 173.00 167.50 195.70 182.10 241.00 3006 2273.00 2337.00 2848.00 3430.00 3492,00 3002 49.90 59.70 84.10 100.00 63.80 4002 346.00 426.00 432.00 555.00 547.00 4003 2182,00 2495,00 2320.00 2731.00 2668,00 4004 238.00 290.00 294.00 236.00 319.00 4005 114.10 150.30 216.00 353.50 568.10 4009 1589,00 1458.00 1342.00 1167.00 1084,00 4011 481.20 534.70 690.40 627.40

- week, b - day.

Pain hindrances were assessed by a system of brief accounting for suffering (VpeG Rush [pteGiog. BPR. PI was used to evaluate pain hindrances in the following: (a) general activity, (b) mood, (c) ability to walk, (b) normal work, ( f) relationships with other people, (D) sleep and (e) enjoyment of life. The total indicator of pain interference is calculated as (average indicator of questions with the answer received) x (7 / number of questions with the answer received). If 4 or more questions remain unanswered, total pain interference is set as absent yuschy.

The dynamics of pain assessment during drug administration is shown in FIG. 4B and 5B. When comparing with

- 14 032117 by the dynamics of PSA (Fig. 4A, 5A) it can be seen that during treatment Ε17ΌΙ6, pain relief correlates with a decrease in PSA levels. The increase in pain index in FIG. 4B between the 276th and 296th days was caused by gout phenomena unrelated to the effect of the drug.

Example 8. The reduction of the primary tumor and tumor lesions of the soft tissues (lymph nodes).

To determine whether the disease is stable or treatable, a bone scan and a CT scan were performed. In individuals with progression in bones or CT scans according to the criteria of PCAC2 and ΕΕί.Ί8Τ, treatment was discontinued.

In some patients, a clinically significant decrease in the primary tumor (in the prostate) and lesions in the target organs (in the lymph nodes) was found. CT scan results illustrating the contraction of both the primary tumor and the lesions in the nodes are shown in FIG. 6.

Table 6 Patient No. 2001, dose of 500 mg every 2 weeks, partial remission of the primary tumor and accessible lesions, measured by CT scans

Patient No. 2001 08/17/2009 before a dose 09/29/2009 12/28/2009 03/25/2010 Lymph nodes (LU) right inguinal 38x36 38x28 16x13 17x10 Lu retro 30x19 31 x 19 16x5 8x3 LU - iliac right 22x15 24 x 16 13x4 10x4 Primary prostate tumor 4.7 x 5 tbsp 3.1 x 3.3 tbsp

The response to the treatment was evaluated on the basis of the ΚΤ / сканирования scan and documented according to the evaluation criteria for Kekropke Ενηΐυηΐίοη C.’n1epa ίη 8ο1ίά Titoga solid tumors (ΚΕΟΙ8Τ). At the initial examination, tumor lesions were classified as accessible to measurement or inaccessible to measurement as accurately as possible to measure the size of the lesion in at least one direction. Disease progression was defined as at least a 20% increase in the sum of the largest diameters of measurable lesions compared to the lowest level or the appearance of new lesions.

Secondary efficacy assessments were carried out during the initial examination and during the study (according to PSA and the general parameter of pain interference) or at the 6th week (assessment of the response to treatment), respectively, at intervals of 4 or 12 weeks, if treatment of patients continued beyond the 6th weeks.

LIST OF SEQUENCES <110> MERCK PATENT GMBH

<120> APPLICATION OF ANTIBODY ΌΤ17Ε6 TO ALPHA-ТЕ INTEGRIN IN THE PRODUCTION OF LE-

OF MENTAL MEDICINE AND TREATMENT OF PROSTATE CANCER, METHOD OF TREATMENT OF PROSTATURE CANCER RESISTANT TO CASTRATION OF CANCER (SERO), METHOD FOR REDUCING THE PSA LEVEL, METHOD FOR REDUCING THE PAIN MANIFESTED IN PROSTATE CANCER

<130> EP11001135.0 <140> <141> PCT / EP2012 / 000548 2012-02-07 <150> <151> EP11001135.0 2011-02-11 <160> 7 <170> RaEePn νθΓ ^ <210> <211> <212> <213> one 214 PRT Artificial sequence

- 15 032 117 <220>

<223> Provisions 24-34 of SBK1, Provisions 50-56 of SVK2, Provisions 89-97 of SVK.3, Provisions 1-107 of the variable region with UPC sections> light chain <400> 1

Azr one 11th O1p Meb Tht five O1p 5eg Rgo 5eg 5eg ten Bie 5eg A1a 5eg Ya1 15 O1u Azr Agd Ya1 Tht 11th Tht Suz Agd A1a 5eg O1p Azr 11th 5eg Azp Tug 20 25 thirty Bie A1a Tgr Tug O1p O1p Bz Rgo O1u Bz A1a Rgo Bz Bie Bie 11th 35 40 45 Tug Tug Tht 5eg Bz 11th H1z 5eg O1u Ya1 Rgo 5eg Agd Pb 5eg O1u 50 55 60 5eg O1u 5eg O1u Tht Azr Tug Tht Pb Tht 11th 5eg 5eg Bie O1p Rgo 65 70 75 80 O1i Azr 11th A1a Tht Tug Tug Suz O1p O1p O1u Azp Tht Pb Rgo Tug 85 90 95 Tht Pb O1u O1p O1u Tht Bz Ya1 O1i 11th Bz Agd Tht Ya1 A1a A1a 100 105 110 Rgo 5eg Ya1 Pb 11th Pb Rgo Rgo 5eg Azr O1i O1p Bie Bz 5eg O1u 115 120 125 Tht A1a 5eg Ya1 Ya1 Suz Bie Bie Azp Azp Pb Tug Rgo Agd O1i A1a 130 135 140 Bz Ya1 O1p Tgr Bz Ya1 Azr Azp A1a Bie O1p 5eg O1u Azp 5eg O1p 145 150 155 160 O1i 5eg Ya1 Tht O1i O1p Azr 5eg Bz Azr 5eg Tht Tug 5eg Bie 5eg 165 170 175 5eg Tht Bie Tht Bie 5eg Bz A1a Azr Tug O1i Bz H1z Bz Ya1 Tug 180 185 190 A1a Suz O1i Ya1 Tht NGZ O1p O1u Bie 5eg 5eg Rgo Ya1 Tht Bz 5eg 195 200 205

Rye Azp Agd O1u O1i Suz

210

- 16 032117 <210> 2 <211> 447 <212> PRT <213> Artificial sequence <220>

<223> Provisions 31 - 35 SPK1, Provisions 50 - 53 SPK2, Provisions 99 107 SPK3, Provisions 217 - 231 of the hinged section 1dO1, Provisions 296

297 substitutions within the 1dO2 region; Provisions 1 to 118 represent variable regions with SEC sections of the heavy chain <400> 2

O1p UA1 one O1n bie O1p five O1p Running O1u O1u O1i ten Bie A1a Bz Rgo O1u 15 A1a Run Ya1 Bz Ya1 Run Suz Bz A1a Run O1u Tug Tht Pb Run Run Pb 20 25 thirty Tgr Meb H1z Tgr Ya1 Agd O1p A1a Rgo O1u O1p O1u Bie O1i Tgr 11th 35 40 45 O1u Tug 11th Azp Rgo Agd Run O1u Tug Tht O1i Tug Azp O1i 11th Pb 50 55 60 Agd Azr Bz A1a Tht Meb Tht Tht Azr Tht Run Tht Run Tht A1a Tug 65 70 75 80 Meb O1i Bie Run Run Bie Agd Run O1i Azr Tht A1a Ya1 Tug Tug Suz 85 90 95 A1a Run Pb Bie O1u Agd O1u A1a Meb Azr Tug Tgr O1u O1p O1u Tht 100 105 110 Tht Ya1 Tht Ya1 Run Run A1a Run Tht Bz O1u Rgo Run Ya1 Pb Rgo 115 120 125 Bie A1a Rgo Suz Run Agd Run Tht Run O1i Run Tht A1a A1a Bie O1u 130 135 140 Suz Bie Ya1 Bz Azr Tug Pb Rgo O1i Rgo Ya1 Tht Ya1 Run Tgr Azp 145 150 155 160 Run O1u A1a Bie Tht Run O1u Ya1 H1z Tht Pb Rgo A1a Ya1 Bie O1p 165 170 175 Run Run O1u Bie Tug Run Bie Run Run Ya1 Ya1 Tht Ya1 Rgo Run Run 180 185 190 Azp Pb O1u Tht O1p Tht Tug Tht Suz Azp Ya1 Azr NGZ Bz Rgo Run

- 17 032117

195

200

205

Azp Bj 210 Bz Ya1 Azr Bz Bj 215 Ya1 O1i Rgo Bz 5eg 220 5eg Azr Bz Bj H1z Bj Suz Rgo Rgo Suz Rgo A1a Rgo Rgo Ya1 A1a O1u Rgo 5eg Ya1 225 230 235 240 Ръе Bie Ръе Rgo Rgo Bz Rgo Bz Azr Bj Bie Me 11th 5eg Agd Bj 245 250 255 Rgo O1i Ya1 Bj Suz Ya1 Ya1 Ya1 Azr Ya1 5eg H1z O1i Azr Rgo O1i 260 265 270 Ya1 O1p Ръе Azp Tgr Tug Ya1 Azr O1u Ya1 O1i Ya1 H1z Azp A1a Bz 275 280 285 Bj Bz Rgo Agd O1i O1i O1p A1a O1p 5eg Bj Ръе Agd Ya1 Ya1 5eg 290 295 300 Ya1 Bie Bj Ya1 Ya1 H1z O1p Azr Tgr Bie Azp O1u Bz O1i Tug Bz 305 310 315 320 Suz Bz Ya1 5eg Azp Bz O1u Bie Rgo A1a Rgo 11th O1i Bz Bj 11th 325 330 335 5eg Bz Bj Bz O1u O1p Rgo Agd O1i Rgo O1p Ya1 Tug Bj Bie Rgo 340 345 350 Rgo 5eg Agd O1i O1i Me Bj Bz Azp O1p Ya1 5eg Bie Bj Suz Bie 355 360 365 Ya1 Bz O1u Ръе Tug Rgo 5eg Azr 11th A1a Ya1 O1i Tgr O1i 5eg Azp 370 375 380 O1u O1p Rgo O1i Azp Azp Tug Bz Bj Bj Rgo Rgo Me Bie Azr 5eg 385 390 395 400 Azr O1u 5eg Ръе Ръе Bie Tug 5eg Bz Bie Bj Ya1 Azr Bz 5eg Agd 405 410 415 Tgr O1p O1p O1u Azp Ya1 Ръе 5eg Suz 5eg Ya1 Me H1z O1i A1a Bie 420 425 430 H1z Azp H1z Tug Bj O1p Bz 5eg Bie 5eg Bie 5eg Rgo O1u Bz 435 440 445

- 18 032117 <210> 3 <211> 15 <212> PRT <213> Artificial sequence <220>

<223> no comments <400> 3

O1i Rgo Luz Running Run Azr Luz Tg H13 Tg Suz Rgo Rgo Suz Rgo

5 1015

<210> <211> <212> <213> four eleven PRT Artificial sequence

<220>

<223> Position 6 - one or more than one position <400> 4 mutated

Tgr O1y O1p O1y Tg Run Ya1 Tg Ya1 Run Run

510

<210> <211> <212> <213> five thirty PRT Artificial sequence

<220>

<223> Positions 9, 13, 20 - one or more than one position <400> is mutated 5

О1п Уа1 О1п Лей О1п О1п Running O1u A1a O1i Ley A1a O1i Rgo O1u A1a one five ten 15

Run Wa1 Luz Meb Run Suz Luz A1a Run O1u Tug Tg Pb Run 20 25 thirty

<210> 6 <211> 14 <212> PRT <213> Artificial sequence <220>

<223> Positions 3, 5 - mutated one or more than one position <400> 6

Tgr Va1 Luz O1n Agd Rgo O1y O1n O1u Ley O1 and Tgr 11e O1u

5 10

<210> 7 <211> 32 <212> PRT

- 19 032 117 <213> Artificial sequence <220>

<223> Positions 6, 10, 16, 19, 21, 25 - one or more than one position <400> is mutated

Luz A1a Teg Meb Tg A1a Azr Teg Running Running Running TAG A1a Tug Meb O1p one five ten 15

Ley Run O1y Ley Tag Run O1 and Azr Run A1a Wa1 Tug Tug Suz A1a Run 20 25 thirty

Claims (34)

CLAIM 1. The use of antibodies ΌΙ17Ε6 to integrin αν or its biologically active variant or modification, where the specified variant or modification contains a constant region that is at least 80-98% identical in amino acid sequence to the constant region ΌΙ17ΌΙ6 in the manufacture of a medicinal product for the treatment of patients suffering from castration-resistant prostate cancer (SIRS). 2. The use of antibodies ΌΙ17Ε6 to integrin αν or its biologically active variant or modification, where the specified variant or modification contains a constant region, which is at least 80-98% identical in amino acid sequence to the constant region ΌΙ17Ε6 for the treatment of patients suffering from castration-resistant cancer prostate (SIRS). 3. The use according to claims 1, 2, where the cancer is metastatic. 4. The use according to claim 3, where the cancer is associated with metastases in the lymph nodes. 5. The use according to claim 3 or 4, where the cancer is associated with bone metastases. 6. The use according to any one of claims 1 to 5, wherein the biologically active variant or modification comprises the variable regions of the heavy and light chains of Ε17 ,6, which are at least 98% identical in amino acid sequence to the variable regions of ΌΙ17Ε6. 7. The use according to claim 6, where the specified antibody ΌΙ17Ε6 contains in the frame regions of the heavy chain one or more modifications: EC1: 0ν06003ΘΑΕ6ΑΕΡ6Α3νΚΜ30ΚΑ30ΥΤΡ3 (Zeo Yu Νο. 16) EC2: ΆΛ / ΚΟΚΡΟΟΟίΕΆΊΟ (8Е0 Yu Νο. 17) YBC: Κ.ΑΤΜΤΑϋΤ555ΤΑΥΜ2ί50ίΤ5Εϋ3ΑνΥΥ0Α5 (ЗОО I ϋ Νο. 18) EK4: ννΟΟΘΤδντνεε (ЗЕО Ю Νο. 19), where one or more of the bold and underlined positions are mutated and differ from the corresponding initial sequence. 8. The use according to any one of claims 1 to 7, wherein the biologically active variant or modification of the ΌΙ17Ε6 antibody contains a constant region that is at least 90% identical in amino acid sequence to the constant region ΌΙ17Ε6. 9. The use of claim 8, where the specified antibody ΌΙ17Ε6 contains the constant region of the human Ι§01 instead of the human Ι§02 or the hinge portion of the human Ι§02 instead of the hinge portion of the human Ι§01. 10. A method of treating patients suffering from castration-resistant prostate cancer (SIRS), comprising administering an anti-integrin αv antibody ΌΙ17Ε6 or a biologically active variant or modification thereof, wherein said variant or modification contains a constant region that is at least 80-98% identical according to the amino acid sequence of the constant region ΌΙ17Ε6. 11. The method according to claim 10, where the amount of prostate-specific antigen (PSA) is reduced during treatment by more than 10 times compared with the amount before treatment with antibodies. 12. The method according to claim 11, where the reduction in the number of PSA is achieved within 4-6 months of treatment. 13. The method according to any one of paragraphs.10-12, where the number of circulating tumor cells (CTC) is reduced during treatment with antibodies. 14. The method according to any one of claims 10 to 13, where castration-resistant prostate cancer is metastatic and where the prostate has been removed from the patient before treatment. 15. The method according to any one of claims 10-14, where the patient has previously undergone chemotherapy treatment - 20 032117 by singing means and / or radiation. 16. The method according to any one of paragraphs.10-15, where the effective dose of antibodies is 500-1000 mg every two weeks. 17. The method according to clause 16, where the effective dose is administered as a single dose. 18. The method according to any one of claims 10-17, wherein the antibodies are administered as monotherapy. 19. The method according to any one of claims 10-18, wherein the biologically active variant or modification comprises variable regions of the heavy and light chains of ΌΙ17Ε6, which are at least 98% identical in amino acid sequence to the variable regions of ΌΙ17ΌΙ6. 20. The method according to claim 19, where the specified antibody ΌΙ17Ε6 contains in the frame regions of the heavy chain one or more modifications: EC1: 0ν0Ε0080ΑΕΙ_ΑΕΡ0Α8νΚΜ80ΚΑ8ΘΥΤΕ8 (Zeo Yu Νο. 16) EC2: 'ΛΛ / ΚΟΡΡΰΟΰΙ.Ε'Λ'ΙΘ (Zeo Yu Νο. 17) ERZ: ΚΑΤΜΤΑ0Τ383ΤΑΥΜ2ΕδΘΕΤ3Ε08ΑνΥΥ0Α3 (Zeo Yu Νο. 18) EP4: νν000Τ8ντν88 (8ЕО Ю Νο. 19), where one or more of the bold and underlined positions are mutated and differ from the corresponding initial sequence. 21. The method according to any one of paragraphs.10-20, where the biologically active variant or modification of the antibody ΌΙ17Ε6 contain a constant region that is at least 90% identical in amino acid sequence to the constant region ΌΙ17Ε6. 22. The method according to item 21, where the specified antibody ΌΙ17Ε6 contains a constant region of the human [cS1 instead of human ΙβΟ2 or the hinged portion of the human ΙβΟ2 instead of the hinged portion of the human Ι§Θ1. 23. The method according to any one of claims 15 to 22, wherein the patient's SCRS progresses after chemotherapy. 24. The method according to any one of claims 10-23, wherein castration-resistant prostate cancer is metastatic and the patient is treated after a prostatectomy or other prostate cancer-related surgery or radiotherapy. 25. The method according to any one of claims 10-24, wherein the antibody treatment further comprises sequential or simultaneous administration of a gonadotropin-releasing hormone agonist or antagonist (antiandrogen therapy). 26. The method according to any one of claims 10 to 25, wherein the antibody treatment further comprises sequential or simultaneous administration of radiation or administration of a cytostatic or cytotoxic agent selected from the group consisting of a chemotherapeutic agent, a tyrosine kinase inhibitor and an angiogenesis inhibitor. 27. The method according to p, where the specified tyrosine kinase inhibitor is an antibody to ΕΦΒ, selected from the group consisting of antibodies to ΕΟΕΒ. antibodies to Neg2 and antibodies to Neg3, and the indicated angiogenesis inhibitor is an αν integrin inhibitor. 28. A method for reducing PSA levels in a patient in need of castration suffering from castration-resistant prostate cancer (SCRS), wherein said method comprises administering to said patient an antibody ΌΙ17ν6 to integrin αν or a biologically active variant or modification thereof, wherein said variant or modification contains a constant region , which is at least 80-98% identical in amino acid sequence to the constant region ΌΙ17Ε6, and the effective dose of the indicated antibody is 500-1500 mg, administered every two weeks. 29. The method according to p, where the effective dose is administered as a single dose. 30. The method according to p. 28 or 29, where the patient suffers from castration-resistant prostate cancer (SCRS). 31. The method according to clause 30, where the cancer metastasizes to bone and / or tissue of the lymph nodes. 32. The method according to claims 28-31, wherein said method comprises reducing PSA level in a patient suffering from prostate cancer during treatment of said patient with said antibody or said biologically active variant or antibody modification by more than 10 times compared with PSA level before administration said antibody or said biologically active variant or antibody modification. 33. A method of reducing pain in a patient in need, manifested in SCRS, accompanied by metastases in the bones and / or lymph nodes, comprising administering to the indicated patient an antibody ΌΙ17ΌΙ6 to integrin αν or its biologically active variant or modification, wherein said variant or modification contains a constant region which is at least 80-98% identical in amino acid sequence to the constant region ΌΙ17Ε6, and the effective dose of the indicated antibodies or the specified biologically active variant or modification is 500-1500 mg administered every two weeks. 34. The method according to clause 33, where the method includes reducing the level of PSA in the patient during treatment by more than 10 times compared with the level of PSA in the patient before starting this method. - 21 032117